Diabetic retinopathy is mainly a vascular disease which first manifests itself by several histopathological lesions related to the integrity of capillary walls, including basement membrane thickening, loss of mural cells, and endothelial cell proliferation. We now find that there is another diabetes-related alteration in capillary walls which results in fewer mural-to- endothelial cell contacts, and may cause endothelial cell proliferation. Normally, junctional regions which permit cell- membrane-to-cell-membrane contacts between mural and endothelial cells occur frequently. They appear as fenestrae in the thick basement membranes which separate the plasma membranes of the mural and endothelial cells over most of their juxtaposed surfaces. In galactose-fed rats there is a significant decrease in the number of junctional regions. After 28 months of normal diet there was a mean of 1.0 (range 1-6) junctional region per ultrathin transection of rat retinal capillaries, whereas, rats fed 50% galactose had less than half as many (mean = 0.3). When an aldose reductase inhibitor was added to the galactose diet the number of junctional regions approached normal (mean = 0.8). Therefore, as with several other diabetic complications, the decrease in cell- to-cell contacts in capillary walls is prevented by inhibition of aldose reductase activity. The mechanism of cell contact loss will be investigated using cell culture. Aldose reductase inhibitors are becoming increasingly useful in studies related to the possible prevention of diabetic retinopathy.